The dual model of cyclooxygenase (COX) has been the rationale for developing selective COX-2 inhibitors to treat inflammatory pain and avoid the adverse gastrointestinal effects of COX-1 suppression by traditional NSAIDs (tNSAIDs). However, increasing evidence indicates that this model is oversimplified to explain the observed differences in therapeutic and adverse effects among COX-2 inhibitors in clinical and experimental studies. New insights into the biological properties of COX-2 and its response pathway challenge the hypothesis that COX-2 is simply pro-inflammatory and inhibition of COX-2 solely prevents the development of inflammation and ameliorates inflammatory pain. Recent clinical trials reveal that COX-2 inhibition by coxibs is associated with an increased risk of cardiovascular events. While the mechanisms underlying the adverse effects of COX-2 inhibitors have been attributed to an imbalance of prostaglandin I2 and thromboxane A2, it is still unclear whether the adverse effects of coxibs are solely the result of COX-2 inhibition. Using microarray gene expression analysis, we have demonstrated that inhibition of COX-2 by rofecoxib modulates multiple gene expression pathways besides COX-2 cascade in a well-characterized clinical model of acute inflammation (Wang et al., 2006a,b). Inhibition of COX-2, in the presence of acute inflammation, induces changes in gene expression related to the matrix metalloproteinase (MMP) pathway in humans. Our findings indicate a more complex role of COX-2 in the inflammatory cascade and that COX-2-independent pathways are also involved in the rofecoxib-induced anti-inflammatory and analgesic effects at the gene expression level. These changes may impair inflammatory resolution via degradation and remodeling of the extracellular matrix and contribute to the adverse effects attributed to COX-2 inhibition in clinical observations. These results may provide an alternative hypothesis for the therapeutic and the adverse effects attributed to selective inhibition of COX-2. Comprehensive study of the reciprocal interplay between patient reported inflammatory symptoms, signatures of gene/protein expression and the selective anti-inflammatory drugs may lead to development of biomarkers for therapeutic responses and adverse events attributed to coxibs in the treatment of inflammatory disorders.